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Crizotinib and Combination Chemotherapy in Treating Younger Patients With Relapsed or Refractory Solid Tumors or Anaplastic Large Cell Lymphoma

Primary Purpose

Childhood Solid Neoplasm, Recurrent Childhood Anaplastic Large Cell Lymphoma, Recurrent Neuroblastoma

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Crizotinib
Cyclophosphamide
Dexrazoxane Hydrochloride
Doxorubicin Hydrochloride
Laboratory Biomarker Analysis
Pharmacological Study
Questionnaire Administration
Topotecan Hydrochloride
Vincristine Sulfate
Sponsored by
Children's Oncology Group
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Childhood Solid Neoplasm focused on measuring Crizotinib, Chemotherapy, Solid Tumors, Anaplastic Large Cell Lymphoma

Eligibility Criteria

13 Months - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients must have had histologic verification of malignancy at original diagnosis or relapse; all patients with relapsed or refractory solid tumors or anaplastic large cell lymphoma (ALCL) are eligible except for patients with primary or metastatic central nervous system (CNS) tumors or patients with primary cutaneous ALCL
  • Patients must have either measurable or evaluable disease
  • Patient?s current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life
  • Karnofsky >= 60% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age; Note: patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
  • Patients must have fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy

    • Myelosuppressive chemotherapy:

      • Solid tumors: at least 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea)
      • ALCL:

        • Patients with ALCL who relapse while receiving standard maintenance chemotherapy will not be required to have a waiting period before enrollment onto this study
        • Patients who relapse while they are not receiving standard maintenance therapy, must have fully recovered from all acute toxic effects of prior therapy; at least 14 days must have elapsed after the completion of cytotoxic therapy
    • Hematopoietic growth factors: at least 14 days after the last dose of a long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth factor; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair
    • Biologic (anti-neoplastic agent): at least 7 days after the last dose of a biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair
    • Immunotherapy: at least 42 days after the completion of any type of immunotherapy, e.g. tumor vaccines
    • Monoclonal antibodies: at least 3 half-lives of the antibody after the last dose of a monoclonal antibody
    • Radiation therapy (XRT):

      • Solid tumors: at least 14 days after local palliative XRT (small port); >= 6 weeks must have elapsed since treatment with therapeutic doses of metaiodobenzylguanidine (MIBG); at least 150 days must have elapsed if prior total body irradiation (TBI), craniospinal XRT or if >= 50% radiation of pelvis; at least 42 days must have elapsed if other substantial bone marrow (BM) radiation
      • ALCL: at least 14 days after local palliative XRT (small port); at least 84 days must have elapsed if prior TBI, craniospinal XRT or if >= 50% radiation of pelvis; at least 42 days must have elapsed if other substantial BM radiation
    • Stem cell infusion without TBI: no evidence of active graft vs. host disease and at least 84 days must have elapsed after transplant and >= 42 days for autologous stem cell infusion after iodine (I)131-MIBG therapy
    • Patients must not have received prior therapy with crizotinib
    • Prior anthracycline dose: patients with a total lifetime cumulative anthracycline dose of > 650 mg/m^2 at the time of enrollment are not eligible for Part B of the study
  • For patients with solid tumors or ALCL without known bone marrow involvement:

    • Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
    • Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
  • Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions); these patients will not be evaluable for hematologic toxicity; if dose-limiting hematologic toxicity is observed, all subsequent patients enrolled must be evaluable for hematologic toxicity
  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

    • Age 1 to < 2 years: 0.6 mg/dL
    • Age 2 to < 6 years: 0.8 mg/dL
    • Age 6 to < 10 years: 1 mg/dL
    • Age 10 to < 13 years: 1.2 mg/dL
    • Age 13 to < 16 years: 1.5 mg/dL (males) and 1.4 mg/dL (females)
    • Age >= 16 years: 1.7 mg/dL (males) and 1.4 mg/dL (females)
  • Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age
  • Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 110 U/L; for the purpose of this study, the ULN for SGPT is 45 U/L
  • Serum albumin >= 2 g/dL
  • Corrected QT interval (QTc) =< 480 msec
  • For patients on Part B: shortening fraction of >= 27% by echocardiogram or ejection fraction of >= 50% by gated radionuclide study
  • All patients and/or their parents or legally authorized representatives must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines
  • Part C: Patients must have a body surface area (BSA) >= 1.07 m^2 at the time of study enrollment
  • Tumor tissue must be sent; if tumor tissue is unavailable, the study chair must be notified prior to enrollment

Exclusion Criteria:

  • Pregnant or breast-feeding women will not be entered on this study; pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method during treatment and for 3 months after stopping treatment
  • Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible
  • Patients who are currently receiving another investigational drug are not eligible
  • Patients who are currently receiving other anti-cancer agents are not eligible
  • Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial
  • Patients chronically receiving medications known to be metabolized by cytochrome P 450, family 3, subfamily A, polypeptide 4 (CYP3A4) and with narrow therapeutic indices including pimozide, aripiprazole, triazolam, ergotamine and halofantrine are not eligible; the topical use of these medications (if applicable) is allowed
  • Patients chronically receiving drugs that are known potent CYP3A4 inhibitors within 7 days prior to study enrollment, including but not limited to ketoconazole, itraconazole, miconazole, clarithromycin, erythromycin, ritonavir, indinavir, nelfinavir, saquinavir, amprenavir, delavirdine, nefazodone, diltiazem, verapamil, and grapefruit juice are not eligible; the topical use of these medications (if applicable), e.g. 2% ketoconazole cream, is allowed
  • Patients chronically receiving drugs that are known potent CYP3A4 inducers within 12 days prior to study enrollment, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, tipranavir, ritonavir, and St. John?s wort are not eligible; the topical use of these medications (if applicable) is allowed
  • Patients who have an uncontrolled infection are not eligible
  • Patients who have received a prior solid organ transplantation are not eligible
  • Patients who have a primary or metastatic CNS tumor at the time of study enrollment are not eligible; a prior history of metastatic CNS tumor is allowed as long as there is no evidence of CNS disease at study enrollment
  • Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible
  • Parts A and B: Patients who are able to swallow liquid or use a nasogastric or gastrostomy (G) tube are eligible
  • Part C: Patients must be able to swallow intact capsules

Sites / Locations

  • Children's Hospital of Alabama
  • Children's Hospital Los Angeles
  • Children's Hospital of Orange County
  • UCSF Medical Center-Parnassus
  • UCSF Medical Center-Mission Bay
  • Children's Hospital Colorado
  • Children's National Medical Center
  • Children's Healthcare of Atlanta - Egleston
  • Lurie Children's Hospital-Chicago
  • Riley Hospital for Children
  • C S Mott Children's Hospital
  • University of Minnesota/Masonic Cancer Center
  • Washington University School of Medicine
  • Columbia University/Herbert Irving Cancer Center
  • Cincinnati Children's Hospital Medical Center
  • Oregon Health and Science University
  • Children's Hospital of Philadelphia
  • Children's Hospital of Pittsburgh of UPMC
  • St. Jude Children's Research Hospital
  • Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
  • Seattle Children's Hospital
  • Children's Hospital of Wisconsin
  • Hospital for Sick Children

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Part A (crizotinib, cyclophosphamide, topotecan hydrochloride)

Part B (crizotinib, vincristine, dexrazoxane, doxorubicin)

Part C (crizotinib, cyclophosphamide, topotecan hydrochloride)

Arm Description

Patients receive crizotinib (oral solution) PO BID on days 1-21, cyclophosphamide IV QD on days 1-5, and topotecan hydrochloride IV QD on days 1-5. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. (closed to accrual 10/3/14)

Patients receive crizotinib (oral solution) PO BID as in Part A. Patients also receive vincristine sulfate IV on day 1, dexrazoxane hydrochloride IV on day 1, and doxorubicin hydrochloride IV over 15 minutes on day 1. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. (closed to accrual 10/3/14)

Patients receive crizotinib (capsule formulation) PO BID, cyclophosphamide IV QD, and topotecan hydrochloride IV QD as in Part A. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

Incidence of adverse events
A descriptive summary of all toxicities will be reported as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Maximum tolerated dose (MTD) of crizotinib
The MTD of crizotinib administered with combination chemotherapy based on the incidence of dose-limiting toxicity (DLT) at which fewer than one-third of patients experience DLT, as assessed by NCI CTCAE version 4.0.

Secondary Outcome Measures

Time to maximum plasma concentration (Tmax)
Crizotinib plasma concentrations will be measured at a centralized laboratory using a validated liquid chromatography/tandem mass spectrometry assay. Pharmacokinetic (PK) parameters (Tmax, peak concentration [Cmax], half-life [t1/2], area under the curve [AUC], plasma clarance [Cl/F]) of crizotinib will be calculated using standard non-compartmental or compartmental methods and summarized with descriptive summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).
Peak concentration (Cmax)
Crizotinib plasma concentrations will be measured at a centralized laboratory using a validated liquid chromatography/tandem mass spectrometry assay. PK parameters (Tmax, Cmax, t1/2, AUC, Cl/F) of crizotinib will be calculated using standard non-compartmental or compartmental methods and summarized with descriptive summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).
Terminal phase half-life (t1/2)
Crizotinib plasma concentrations will be measured at a centralized laboratory using a validated liquid chromatography/tandem mass spectrometry assay. PK parameters (Tmax, Cmax, t1/2, AUC, Cl/F) of crizotinib will be calculated using standard non-compartmental or compartmental methods and summarized with descriptive summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).
Area under the concentration
Crizotinib plasma concentrations will be measured at a centralized laboratory using a validated liquid chromatography/tandem mass spectrometry assay. PK parameters (Tmax, Cmax, t1/2, AUC, Cl/F) of crizotinib will be calculated using standard non-compartmental or compartmental methods and summarized with descriptive summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).
Plasma Clearance (CI/F)
Crizotinib plasma concentrations will be measured at a centralized laboratory using a validated liquid chromatography/tandem mass spectrometry assay. PK parameters (Tmax, Cmax, t1/2, AUC, Cl/F) of crizotinib will be calculated using standard non-compartmental or compartmental methods and summarized with descriptive summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).
Response rate
Disease Response Rate (occurrence of PR/CR) assessed according to Response Evaluation Criteria in Solid Tumors version 1.1 Will be reported descriptively.

Full Information

First Posted
May 24, 2012
Last Updated
February 22, 2019
Sponsor
Children's Oncology Group
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT01606878
Brief Title
Crizotinib and Combination Chemotherapy in Treating Younger Patients With Relapsed or Refractory Solid Tumors or Anaplastic Large Cell Lymphoma
Official Title
A Phase 1 Study of Crizotinib in Combination With Conventional Chemotherapy for Relapsed or Refractory Solid Tumors or Anaplastic Large Cell Lymphoma
Study Type
Interventional

2. Study Status

Record Verification Date
January 2019
Overall Recruitment Status
Completed
Study Start Date
April 29, 2013 (Actual)
Primary Completion Date
December 31, 2018 (Actual)
Study Completion Date
December 31, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Children's Oncology Group
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This phase I trial studies the side effects and the best dose of crizotinib when given together with combination chemotherapy in treating younger patients with solid tumors or anaplastic large cell lymphoma that has returned or does not respond to treatment. Crizotinib may stop the growth of tumor or cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cyclophosphamide, topotecan hydrochloride, dexrazoxane hydrochloride, doxorubicin hydrochloride, and vincristine sulfate, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving crizotinib together with combination chemotherapy may be a better treatment for patients with solid tumors or anaplastic large cell lymphoma.
Detailed Description
PRIMARY OBJECTIVES: I. To estimate the recommended phase 2 dose (RP2D) or maximum tolerated dose (MTD) of crizotinib administered orally twice daily in combination with topotecan (topotecan hydrochloride) and cyclophosphamide in children with refractory/relapsed solid tumors or anaplastic large cell lymphoma (ALCL). II. To define and describe the toxicities of crizotinib in combination with topotecan and cyclophosphamide administered on this schedule. III. To estimate the recommended phase 2 dose (RP2D) or maximum tolerated dose (MTD) of crizotinib administered orally twice daily in combination with vincristine (vincristine sulfate) and doxorubicin (doxorubicin hydrochloride)/dexrazoxane (dexrazoxane hydrochloride) in children with refractory/relapsed solid tumors or ALCL. IV. To define and describe the toxicities of crizotinib in combination with vincristine and doxorubicin/dexrazoxane administered on this schedule. V. To characterize the pharmacokinetics of crizotinib in children with relapsed/refractory cancer when combined with either topotecan and cyclophosphamide or vincristine and doxorubicin/dexrazoxane. SECONDARY OBJECTIVES: I. To preliminarily define the antitumor activity of crizotinib in combination with either topotecan and cyclophosphamide or vincristine and doxorubicin/dexrazoxane within the confines of a Phase 1 study. II. To preliminarily examine the relationship between anaplastic lymphoma kinase (ALK) status in patients with neuroblastoma or ALCL and response to crizotinib in combination with either topotecan and cyclophosphamide or vincristine and doxorubicin/dexrazoxane. III. To preliminarily examine the relationship between minimal residual disease (MRD) status and clinical response to crizotinib in combination with either topotecan and cyclophosphamide or vincristine and doxorubicin/dexrazoxane in patients with ALCL. IV. To use a questionnaire to gather preliminary information on the palatability of the oral solution formulation of crizotinib. V. To examine ALK and MET proto-oncogene (c-Met) expression, copy number and mutations status in archival tumor tissue from solid tumor and ALCL patients. VI. To use a questionnaire to gather information on the acceptability of the crizotinib capsule formulation. OUTLINE: This is a dose-escalation study of crizotinib. Patients are assigned to Part A or Part B based on the treating physician's choice and availability of a reservation. After closure of Part A and Part B, patients are assigned to Part C. PART A (CLOSED TO ACCRUAL 10/3/14): Patients receive crizotinib (oral solution) orally (PO) twice daily (BID) on days 1-21, cyclophosphamide intravenously (IV) once daily (QD) on days 1-5, and topotecan hydrochloride IV QD on days 1-5. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. PART B (CLOSED TO ACCRUAL 10/3/14): Patients receive crizotinib (oral solution) PO BID as in Part A. Patients also receive vincristine sulfate IV on day 1, dexrazoxane hydrochloride IV on day 1, and doxorubicin hydrochloride IV over 15 minutes on day 1. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. PART C: Patients receive crizotinib (capsule formulation) PO BID, cyclophosphamide IV QD, and topotecan hydrochloride IV QD as in Part A. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Childhood Solid Neoplasm, Recurrent Childhood Anaplastic Large Cell Lymphoma, Recurrent Neuroblastoma
Keywords
Crizotinib, Chemotherapy, Solid Tumors, Anaplastic Large Cell Lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
46 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Part A (crizotinib, cyclophosphamide, topotecan hydrochloride)
Arm Type
Experimental
Arm Description
Patients receive crizotinib (oral solution) PO BID on days 1-21, cyclophosphamide IV QD on days 1-5, and topotecan hydrochloride IV QD on days 1-5. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. (closed to accrual 10/3/14)
Arm Title
Part B (crizotinib, vincristine, dexrazoxane, doxorubicin)
Arm Type
Experimental
Arm Description
Patients receive crizotinib (oral solution) PO BID as in Part A. Patients also receive vincristine sulfate IV on day 1, dexrazoxane hydrochloride IV on day 1, and doxorubicin hydrochloride IV over 15 minutes on day 1. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. (closed to accrual 10/3/14)
Arm Title
Part C (crizotinib, cyclophosphamide, topotecan hydrochloride)
Arm Type
Experimental
Arm Description
Patients receive crizotinib (capsule formulation) PO BID, cyclophosphamide IV QD, and topotecan hydrochloride IV QD as in Part A. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
Intervention Type
Drug
Intervention Name(s)
Crizotinib
Other Intervention Name(s)
MET Tyrosine Kinase Inhibitor PF-02341066, PF-02341066, PF-2341066, Xalkori
Intervention Description
Given PO
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Dexrazoxane Hydrochloride
Other Intervention Name(s)
Cardioxane, Totect, Zinecard
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Doxorubicin Hydrochloride
Other Intervention Name(s)
5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI), ADM, Adriacin, Adriamycin, Adriamycin Hydrochloride, Adriamycin PFS, Adriamycin RDF, ADRIAMYCIN, HYDROCHLORIDE, Adriamycine, Adriblastina, Adriblastine, Adrimedac, Chloridrato de Doxorrubicina, DOX, DOXO-CELL, Doxolem, Doxorubicin.HCl, Doxorubin, Farmiblastina, FI 106, FI-106, hydroxydaunorubicin, Rubex
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
Pharmacological Study
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
Questionnaire Administration
Intervention Description
Ancillary studies
Intervention Type
Drug
Intervention Name(s)
Topotecan Hydrochloride
Other Intervention Name(s)
Hycamptamine, Hycamtin, SKF S-104864-A, Topotecan HCl, topotecan hydrochloride (oral)
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Vincristine Sulfate
Other Intervention Name(s)
Kyocristine, Leurocristine sulfate, Leurocristine, sulfate, Oncovin, Vincasar, Vincosid, Vincrex, Vincristine, sulfate
Intervention Description
Given IV
Primary Outcome Measure Information:
Title
Incidence of adverse events
Description
A descriptive summary of all toxicities will be reported as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Time Frame
Up to 30 days post-treatment
Title
Maximum tolerated dose (MTD) of crizotinib
Description
The MTD of crizotinib administered with combination chemotherapy based on the incidence of dose-limiting toxicity (DLT) at which fewer than one-third of patients experience DLT, as assessed by NCI CTCAE version 4.0.
Time Frame
21 days
Secondary Outcome Measure Information:
Title
Time to maximum plasma concentration (Tmax)
Description
Crizotinib plasma concentrations will be measured at a centralized laboratory using a validated liquid chromatography/tandem mass spectrometry assay. Pharmacokinetic (PK) parameters (Tmax, peak concentration [Cmax], half-life [t1/2], area under the curve [AUC], plasma clarance [Cl/F]) of crizotinib will be calculated using standard non-compartmental or compartmental methods and summarized with descriptive summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).
Time Frame
Time Frame: Prior to first dose on day 1 of course 1 and at pre-dose (12 hours after last dose), 1, 2, 4, and 6-8 hours post-dose between days 15 and 21 of course 1
Title
Peak concentration (Cmax)
Description
Crizotinib plasma concentrations will be measured at a centralized laboratory using a validated liquid chromatography/tandem mass spectrometry assay. PK parameters (Tmax, Cmax, t1/2, AUC, Cl/F) of crizotinib will be calculated using standard non-compartmental or compartmental methods and summarized with descriptive summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).
Time Frame
Time Frame: Prior to first dose on day 1 of course 1 and at pre-dose (12 hours after last dose), 1, 2, 4, and 6-8 hours post-dose between days 15 and 21 of course 1
Title
Terminal phase half-life (t1/2)
Description
Crizotinib plasma concentrations will be measured at a centralized laboratory using a validated liquid chromatography/tandem mass spectrometry assay. PK parameters (Tmax, Cmax, t1/2, AUC, Cl/F) of crizotinib will be calculated using standard non-compartmental or compartmental methods and summarized with descriptive summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).
Time Frame
Time Frame: Prior to first dose on day 1 of course 1 and at pre-dose (12 hours after last dose), 1, 2, 4, and 6-8 hours post-dose between days 15 and 21 of course 1
Title
Area under the concentration
Description
Crizotinib plasma concentrations will be measured at a centralized laboratory using a validated liquid chromatography/tandem mass spectrometry assay. PK parameters (Tmax, Cmax, t1/2, AUC, Cl/F) of crizotinib will be calculated using standard non-compartmental or compartmental methods and summarized with descriptive summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).
Time Frame
Time Frame: Prior to first dose on day 1 of course 1 and at pre-dose (12 hours after last dose), 1, 2, 4, and 6-8 hours post-dose between days 15 and 21 of course 1
Title
Plasma Clearance (CI/F)
Description
Crizotinib plasma concentrations will be measured at a centralized laboratory using a validated liquid chromatography/tandem mass spectrometry assay. PK parameters (Tmax, Cmax, t1/2, AUC, Cl/F) of crizotinib will be calculated using standard non-compartmental or compartmental methods and summarized with descriptive summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).
Time Frame
Time Frame: Prior to first dose on day 1 of course 1 and at pre-dose (12 hours after last dose), 1, 2, 4, and 6-8 hours post-dose between days 15 and 21 of course 1
Title
Response rate
Description
Disease Response Rate (occurrence of PR/CR) assessed according to Response Evaluation Criteria in Solid Tumors version 1.1 Will be reported descriptively.
Time Frame
Up to 2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
13 Months
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients must have had histologic verification of malignancy at original diagnosis or relapse; all patients with relapsed or refractory solid tumors or anaplastic large cell lymphoma (ALCL) are eligible except for patients with primary or metastatic central nervous system (CNS) tumors or patients with primary cutaneous ALCL Patients must have either measurable or evaluable disease Patient?s current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life Karnofsky >= 60% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age; Note: patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score Patients must have fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy Myelosuppressive chemotherapy: Solid tumors: at least 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea) ALCL: Patients with ALCL who relapse while receiving standard maintenance chemotherapy will not be required to have a waiting period before enrollment onto this study Patients who relapse while they are not receiving standard maintenance therapy, must have fully recovered from all acute toxic effects of prior therapy; at least 14 days must have elapsed after the completion of cytotoxic therapy Hematopoietic growth factors: at least 14 days after the last dose of a long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth factor; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair Biologic (anti-neoplastic agent): at least 7 days after the last dose of a biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair Immunotherapy: at least 42 days after the completion of any type of immunotherapy, e.g. tumor vaccines Monoclonal antibodies: at least 3 half-lives of the antibody after the last dose of a monoclonal antibody Radiation therapy (XRT): Solid tumors: at least 14 days after local palliative XRT (small port); >= 6 weeks must have elapsed since treatment with therapeutic doses of metaiodobenzylguanidine (MIBG); at least 150 days must have elapsed if prior total body irradiation (TBI), craniospinal XRT or if >= 50% radiation of pelvis; at least 42 days must have elapsed if other substantial bone marrow (BM) radiation ALCL: at least 14 days after local palliative XRT (small port); at least 84 days must have elapsed if prior TBI, craniospinal XRT or if >= 50% radiation of pelvis; at least 42 days must have elapsed if other substantial BM radiation Stem cell infusion without TBI: no evidence of active graft vs. host disease and at least 84 days must have elapsed after transplant and >= 42 days for autologous stem cell infusion after iodine (I)131-MIBG therapy Patients must not have received prior therapy with crizotinib Prior anthracycline dose: patients with a total lifetime cumulative anthracycline dose of > 650 mg/m^2 at the time of enrollment are not eligible for Part B of the study For patients with solid tumors or ALCL without known bone marrow involvement: Peripheral absolute neutrophil count (ANC) >= 1000/mm^3 Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions); these patients will not be evaluable for hematologic toxicity; if dose-limiting hematologic toxicity is observed, all subsequent patients enrolled must be evaluable for hematologic toxicity Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows: Age 1 to < 2 years: 0.6 mg/dL Age 2 to < 6 years: 0.8 mg/dL Age 6 to < 10 years: 1 mg/dL Age 10 to < 13 years: 1.2 mg/dL Age 13 to < 16 years: 1.5 mg/dL (males) and 1.4 mg/dL (females) Age >= 16 years: 1.7 mg/dL (males) and 1.4 mg/dL (females) Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 110 U/L; for the purpose of this study, the ULN for SGPT is 45 U/L Serum albumin >= 2 g/dL Corrected QT interval (QTc) =< 480 msec For patients on Part B: shortening fraction of >= 27% by echocardiogram or ejection fraction of >= 50% by gated radionuclide study All patients and/or their parents or legally authorized representatives must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines Part C: Patients must have a body surface area (BSA) >= 1.07 m^2 at the time of study enrollment Tumor tissue must be sent; if tumor tissue is unavailable, the study chair must be notified prior to enrollment Exclusion Criteria: Pregnant or breast-feeding women will not be entered on this study; pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method during treatment and for 3 months after stopping treatment Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible Patients who are currently receiving another investigational drug are not eligible Patients who are currently receiving other anti-cancer agents are not eligible Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial Patients chronically receiving medications known to be metabolized by cytochrome P 450, family 3, subfamily A, polypeptide 4 (CYP3A4) and with narrow therapeutic indices including pimozide, aripiprazole, triazolam, ergotamine and halofantrine are not eligible; the topical use of these medications (if applicable) is allowed Patients chronically receiving drugs that are known potent CYP3A4 inhibitors within 7 days prior to study enrollment, including but not limited to ketoconazole, itraconazole, miconazole, clarithromycin, erythromycin, ritonavir, indinavir, nelfinavir, saquinavir, amprenavir, delavirdine, nefazodone, diltiazem, verapamil, and grapefruit juice are not eligible; the topical use of these medications (if applicable), e.g. 2% ketoconazole cream, is allowed Patients chronically receiving drugs that are known potent CYP3A4 inducers within 12 days prior to study enrollment, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, tipranavir, ritonavir, and St. John?s wort are not eligible; the topical use of these medications (if applicable) is allowed Patients who have an uncontrolled infection are not eligible Patients who have received a prior solid organ transplantation are not eligible Patients who have a primary or metastatic CNS tumor at the time of study enrollment are not eligible; a prior history of metastatic CNS tumor is allowed as long as there is no evidence of CNS disease at study enrollment Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible Parts A and B: Patients who are able to swallow liquid or use a nasogastric or gastrostomy (G) tube are eligible Part C: Patients must be able to swallow intact capsules
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Emily Greengard
Organizational Affiliation
COG Phase I Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's Hospital of Alabama
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35233
Country
United States
Facility Name
Children's Hospital Los Angeles
City
Los Angeles
State/Province
California
ZIP/Postal Code
90027
Country
United States
Facility Name
Children's Hospital of Orange County
City
Orange
State/Province
California
ZIP/Postal Code
92868
Country
United States
Facility Name
UCSF Medical Center-Parnassus
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States
Facility Name
UCSF Medical Center-Mission Bay
City
San Francisco
State/Province
California
ZIP/Postal Code
94158
Country
United States
Facility Name
Children's Hospital Colorado
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Children's National Medical Center
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States
Facility Name
Children's Healthcare of Atlanta - Egleston
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Lurie Children's Hospital-Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Riley Hospital for Children
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
C S Mott Children's Hospital
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
University of Minnesota/Masonic Cancer Center
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Columbia University/Herbert Irving Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Cincinnati Children's Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States
Facility Name
Oregon Health and Science University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Children's Hospital of Pittsburgh of UPMC
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15224
Country
United States
Facility Name
St. Jude Children's Research Hospital
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38105
Country
United States
Facility Name
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Seattle Children's Hospital
City
Seattle
State/Province
Washington
ZIP/Postal Code
98105
Country
United States
Facility Name
Children's Hospital of Wisconsin
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States
Facility Name
Hospital for Sick Children
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1X8
Country
Canada

12. IPD Sharing Statement

Citations:
PubMed Identifier
33095287
Citation
Greengard E, Mosse YP, Liu X, Minard CG, Reid JM, Voss S, Wilner K, Fox E, Balis F, Blaney SM, Adamson PC, Weigel BJ. Safety, tolerability and pharmacokinetics of crizotinib in combination with cytotoxic chemotherapy for pediatric patients with refractory solid tumors or anaplastic large cell lymphoma (ALCL): a Children's Oncology Group phase 1 consortium study (ADVL1212). Cancer Chemother Pharmacol. 2020 Dec;86(6):829-840. doi: 10.1007/s00280-020-04171-4. Epub 2020 Oct 23.
Results Reference
derived

Learn more about this trial

Crizotinib and Combination Chemotherapy in Treating Younger Patients With Relapsed or Refractory Solid Tumors or Anaplastic Large Cell Lymphoma

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